Regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol

Adele Stewart; Biswanath Maity; Simon P Anderegg; Chantal Allamargot; Jianqi Yang; Rory A Fisher

doi:10.1073/pnas.1418795112

Back

Regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol

Journal article

Open access

Peer reviewed

Regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol

Adele Stewart, Biswanath Maity, Simon P Anderegg, Chantal Allamargot, Jianqi Yang and Rory A Fisher

Proceedings of the National Academy of Sciences - PNAS, Vol.112(7), pp.E786-E795

02/17/2015

DOI: 10.1073/pnas.1418795112

PMCID: PMC4343156

PMID: 25646431

Files and links (1)

url

https://doi.org/10.1073/pnas.1418795112View

Published (Version of record) Open Access

Abstract

Alcohol is the most commonly abused drug worldwide, and chronic alcohol consumption is a major etiological factor in the development of multiple pathological sequelae, including alcoholic cardiomyopathy and hepatic cirrhosis. Here, we identify regulator of G protein signaling 6 (RGS6) as a critical regulator of both alcohol-seeking behaviors and the associated cardiac and hepatic morbidities through two mechanistically divergent signaling actions. RGS6(-/-) mice consume less alcohol when given free access and are less susceptible to alcohol-induced reward and withdrawal. Antagonism of GABA(B) receptors or dopamine D2 receptors partially reversed the reduction in alcohol consumption in RGS6(-/-) animals. Strikingly, dopamine transporter inhibition completely restored alcohol seeking in mice lacking RGS6. RGS6 deficiency was associated with alterations in the expression of genes controlling dopamine (DA) homeostasis and a reduction in DA levels in the striatum. Taken together, these data implicate RGS6 as an essential regulator of DA bioavailability. RGS6 deficiency also provided dramatic protection against cardiac hypertrophy and fibrosis, hepatic steatosis, and gastrointestinal barrier dysfunction and endotoxemia when mice were forced to consume alcohol. Although RGS proteins canonically function as G-protein regulators, RGS6-dependent, alcohol-mediated toxicity in the heart, liver, and gastrointestinal tract involves the ability of RGS6 to promote reactive oxygen species-dependent apoptosis, an action independent of its G-protein regulatory capacity. We propose that inhibition of RGS6 might represent a viable means to reduce alcohol cravings and withdrawal in human patients, while simultaneously protecting the heart and liver from further damage upon relapse.

Behavior, Animal

RGS Proteins - genetics

Animals

Conditioning, Operant

Mice

RGS Proteins - physiology

Apoptosis - physiology

Reward

Alcohol Drinking

Cardiomyopathies - etiology

Mice, Knockout

Details

Title: Subtitle: Regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol
Creators: Adele Stewart - Department of Pharmacology and
Biswanath Maity - Department of Pharmacology and
Simon P Anderegg - Department of Pharmacology and
Chantal Allamargot - Central Microscopy Facility, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Jianqi Yang - Department of Pharmacology and
Rory A Fisher - Department of Pharmacology and rory-fisher@uiowa.edu
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.112(7), pp.E786-E795
DOI: 10.1073/pnas.1418795112
PMID: 25646431
PMCID: PMC4343156
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Grant note: CA161882 / NCI NIH HHS R01 CA161882 / NCI NIH HHS 1 S10RR025439-01 / NCRR NIH HHS S10 RR025439 / NCRR NIH HHS T32 MH065215 / NIMH NIH HHS
Language: English
Date published: 02/17/2015
Academic Unit: Core Research Facilities; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040384702771

Metrics

16 Record Views

44 Times Cited - Web of Science